Novel thiophene derivatives as sphingosine-1-phosphate-1 receptor agonists

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

 

The text descriptions are given in facsimile form.

1. A compound selected from the group comprising derivatives of thiophene of the formula (I)

where the ring system And is characterized by the formula

R1means hydrogen, C1-C5alkyl or C1-C5alkoxy,
R2means hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl,
R3means hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropane, -OCH2-(CH2)m-NR31R322-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 3-[4-(2-hydroxyethyl)piperazine-1-yl]propoxy, 2-morpholine-4-ylethoxy, 3-morpholine-4-ylpropionic, 3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidine-2-carboxylic acid is TA)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropane;
R31means hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylation, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxyaryl, 2-amino-ethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl;
R32means hydrogen, methyl or ethyl,
m is 1 or 2;
n is 1; and
R4means hydrogen, (C1-C5)alkyl or halogen,
and its configuration isomers, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric the racemates and mixtures of diastereomeric racemates, and salts of these compounds of formula (I).

2. The compound according to claim 1, where R3means hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n- CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropane, -OCH2-(CH2)m-NR31R322-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 3-[4-(2-hydroxyethyl)piperazine-1-yl]propoxy, 2-morpholine-4-ylethoxy, 3-morpholine-4-ylpropionic, 3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxy 3-[(pyrrolidine-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropane, where R31and R32have the meanings indicated in claim 1.

3. The compound according to claim 1 or 2, where the compound represented by formula (I), means (1R,5S)-isomer derived 1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalene.

4. The compound according to claim 1 or 2, where the compound represented by formula (I), means (1S,5R)-isomer derived 1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalene.

5. The compound according to claim 1 or 2, where the compound represented by formula (I), means a derivative of 5-thiophene-2-yl[1,2,4]oxadiazole.

6. The compound according to claim 1 or 2, where the compound represented by formula (I), means a derivative of 3-thiophene-2-yl[1,2,4]oxadiazole.

7. The compound according to claim 1 or 2, where R1, R2and R4mean hydrogen.

8. The compound according to claim 1 or 2, where R1means hydrogen and R2and R4means methyl group.

9. The compound according to claim 1 or 2, where R1means hydrogen, R2means methyl group and R4means ethyl group.

10. The compound according to claim 1 or 2, where R1means hydrogen, R2means a methoxy group, and R4means chlorine.

11. The compound according to claim 1 or 2, where R3means hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropane, -OCH2-(CH2)m-NR31R 322-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 3-[4-(2-hydroxyethyl)piperazine-1-yl]propoxy, 2-morpholine-4-ylethoxy, 3-morpholine-4-ylpropionic, 3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidine-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropane and where R31and R32defined in claim 1.

12. The compound according to claim 1, where R3means hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH or-CH2-(CH2)n-CONR31R32and where R31and R32defined in claim 1.

13. The compound according to claim 1 or 2, where R3means di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl or-OCH2-(CH2)m-NR31R32where R31means methyl or 2-hydroxyethyl and R32means hydrogen.

14. The connection according to claim 1, where R3means-CH2-(CH2)n-COOH or-CH2-(CH2)n-CONR31R32where R31and R32defined in claim 1.

15. The compound according to claim 1, selected from the group including
4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenol,
2-{4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}ethanol
1-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propan-2-ol,
(2S)-3-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-diol,
(2R)-3-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-diol,
1-methoxy-3-{4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propan-2-ol,
2-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxymethyl}propane-1,3-diol,
3-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propan-1-ol,
dimethyl(2-{4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}ethyl)amine,
2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenol,
2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}ethanol,
1-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}propan-2-ol,
(2S)-3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-who IOL,
(2R)-3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propane-1,2-diol,
1-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}-3-methoxypropan-2-ol,
2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxymethyl}propane-1,3-diol,
3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propan-1-ol,
(2-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}ethyl)-dimethylamine,
3-[3,5-dimethyl-4-(2-pyrrolidin-1 ylethoxy)phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol,
4-(2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} ethyl)morpholine,
3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} Propylamine,
(3-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propyl)methylamine,
(3-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propyl)dimethylamine,
2-(3-{2,6-dim the Tyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propylamino)ethanol,
3-[3,5-dimethyl-4-(3-pyrrolidin-1-yl-propoxy)phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol,
(3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propyl)Propylamine,
2-(3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propylamino)propane-1,3-diol,
N1(3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propyl)ethane-1,2-diamine,
1-(3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy} propyl)pyrrolidin-2-carboxylic acid,
1-(3-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propyl)pyrrolidin-3-carboxylic acid,
2-[4-(3-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propyl)piperazine-1-yl]ethanol,
2-amino-2-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxymethyl}propane-1,3-diol,
(3-{2,6-dimethyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propyl)Isopropylamine,
(3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimet is l-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-3-yl]phenoxy}propyl)(2-ethoxyethyl)amine,
2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenol,
2-{2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenoxy}ethanol,
1-{2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenoxy}propan-2-ol,
3-{2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenoxy}propane-1,2-diol,
3-{2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenoxy}propane-1,2-diol,
2-{2,6-dimethyl-4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol-5-yl]phenoxymethyl}propane-1,3-diol, and
3-(3-triptoreline)-5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)[1,2,4]oxadiazol.

16. The compound according to claim 1, selected from the group including
3-(2,4-acid)-5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol,
3-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol,
4(2-{4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}ethyl)morpholine,
3-{2-ethyl-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5A-tetrahydro-3-thia is ecoprobe[and]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]phenyl}propionic acid,
3-{2-ethyl-6-methyl-4-[5-((1S,5R)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]phenyl}-N-(2-hydroxyethyl)propionamide, and
3-{2-ethyl-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1A,5,5A-tetrahydro-3-talkloop[and]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]phenyl}-R-(2-hydroxy-1-hydroxymethylation)propionamide.

17. Pharmaceutical composition having agonistic activity against receptor S1P1/EDG1, comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

18. The compound according to claim 1 or 2, having agonistic activity against receptor S1P1/EDG1 intended for use as a medicine.

19. The use of compounds according to claim 1 or 2 to obtain a pharmaceutical composition intended for the prevention or treatment of diseases or disorders associated with an activated immune system.

20. Application on p.19 for the prevention or treatment of diseases or disorders selected from the group that includes the rejection of implanted organs such as kidney, liver, heart and lung;
graft-versus-host caused by stem cell transplantation; autoimmune syndromes selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease and Hashimoto thyroiditis, and atopic dermatitis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: I, where R1 is selected from group, consisting of ethyl, 2-fluorethyl and isopropyl; R2 is selected from group, consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6, where R6 represents C1-7-alkyl, amino, phenyl, phenyl, substituted with 1-3 substituents, selected from group, consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl; R3 is selected from group, consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl and -o-tetrahydropyranyl; or R2 and R3 are bound to each other with formation of cycle together with carbon atoms to which they are bound, and R2 and R3 together represent -CH=CH-NH-; R4 is selected from group, consisting of hydrogen, halogen, pyridyl and pyrimidyl; R5 and R5' independently on each other are selected from hydrogen or methyl; A is selected from group, consisting of isphenyl; phenyl, substituted with 1-3 substituents, selected from group, consisting of C1-7-alkyl, C3-7-cycloalkyl, C1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylene-C(O)NR10R11, -C(O)OR10, -C1-7-alkylene-C(O)OR10, -O-C1-7-alkylene-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano- C1-7-alkoxy, fluorphenyl, pyridyl, tetrazolyl and tetrazolyl- C1-7-alkoxy; 1,3-benzodioxolyl; naphtyl; pyrimidinyl; pyridyl, substituted with one or two substituents, selected from group, consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino, C3-7-cycloalkylamino, halogen, cyano, morpholinyl, imidazolyl and -NH-C(O)-R9, where R9 represents C1-7-alkyl or C3-7-cycloalkyl, and indolyl; R10 and R11 independently on each other represent hydrogen or C1-7-alkyl; and to their pharmaceutically accdeptable salts. Invention also relates to pharmaceutical compositions.

EFFECT: obtaining novel biologically active compounds, which are antagonists of somatostatin receptor subtype 5 (SSTR5).

26 cl, 266 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula [I]: where A cycle represents a benzene cycle optionally having substitute(s) different from R1, R1 represents a group of formula RaSO2NH-, RaSO2NH-CH2- or (Rb)(Rc)NSO2-, Ra represents C1-C6 alkyl group, C3-C10cycloalkyl group, an amino group, 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic heteroaryl group containing 1-2 heteroatoms, chosen from oxygen, sulphur and nitrogen atoms, Rb and Rc are identical or different, and each represents hydrogen atom, C1-C6alkyl group or C3-C10cycloalkyl group, one of R2 and R3 represents hydrogen atom, halogen atom or C1-C6alkyl group, and the other represents hydrogen atom, C1-C6alkyl group, C1-C6alkoxycarbonyl group or phenyl group, or both are combined with each other together with the neighbouring carbon atom to form C3-C10cycloalkyl group, X represents oxygen atom, sulphur atom, or formula group of -NR4-; Y represents a group of formula -C(=O)-, -C(=S)- or CH(R5)-; Ar represents optionally substituted 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic group; Q represents a simple bond, C1-C6alkylene group or C2-C6alkenylene group, or its pharmaceutically acceptable salts There are described specific compounds of formula [I], and also intermediate compounds.

EFFECT: presented compounds exhibit affinity to mineralocorticoid receptor (MR) and are applicable for prevention or treatment of various diseases or diseased states associated with such receptor.

11 cl, 54 tbl, 410 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

EFFECT: novel salt form of a dopamine agonist which has advantages, specifically is not hygroscopic, has a crystalline form and has high melting point is obtained and described.

11 cl, 9 ex, 2 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

Mif inhibitors // 2383541

FIELD: chemistry.

SUBSTANCE: there is described compound of formula 1

where R1 represents unsubstituted or substituted (C3-C8)cycloalkyl(C1-C4)alkyl, phenyl(C1-C4)alkyl, (C3-C8)cycloalkyl, phenyl, naphthyl, phenyl condensed with 18-(crown)-6, where substitutes include phenyl, halogen, hydroxy, aminosulfonyloxy, (C1-C4)alkoxy, tri(C1-C6)alkylsilyloxy, halogen(C1-C4)alkyl or halogen(C1-C4)alkoxy, R2 represents hydrogen, hydroxyl, aminosulfonyloxy, (C1-C4)alkoxy, tri(C1-C6)alkylsilyloxy or halogen(C1-C4)alkoxy. Also described is use of the compound for making a medicinal agent and a pharmaceutical composition.

EFFECT: disclosed compounds have macrophage migration inhibitory factor activity (MIF).

8 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

where R1 is hydrogen, alkyl, cycloalkyl, hydroxy group, hydroxyalkyl, alkoxy group, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, alkylsulfonyl, alkylsulfanyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, aminocarbonylalkyl, heterocyclylcarbonylalkyl, alkoxycarbonylalkyl, alkoxyalkylaminocarbonylalkyl, cycloalkylalkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, haloidalkyl, haloidalkoxy group or haloidalkoxyalkyl, R2 is hydrogen, alkyl, cycloalkylalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl, haloidalkoxyalkyl, pyrrolidyl, morpholinyl, thiomorpholinyl, arylalkyl, arylalkoxy group, aryloxy group or heterocyclylalkyl, R3 is hydrogen or alkyl, R4 is hydrogen, alkyl or haloid, R5 is phenyl, naphthyl, piperidyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more substitutes independently selected from alkyl, cycloalkyl, haloid, alkoxy group, nitro group, trifluoromethyl, trifluoromethoxy group, trifluoromethylcarbonyl group, aryl, aryloxy group, alkoxycarbonylalkoxy group and alkylsulfonyl, R6 is hydrogen or alkyl, and their pharmaceutically acceptable salts and esters, under the condition that N-(6-(1,1-dimethylethyl)-2-pyridinyl)-4-methylbenzenesulfamide is excluded, and in cases when R1 is hydrogen or methyl, R2 is not hydrogen or methyl, as well as a pharceutical composition based on these compounds.

EFFECT: novel chemical compounds which can be used in treating and preventing diabetes, obesity and eating disorders are obtained and described.

15 cl, 192 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula ; or their pharmaceutically acceptable salts, where A is phenyl, X is CH2- or C=O; Y is O; k equals 1; m equals 0; R2 and R3 each independently represents hydrogen or alkyl, R4 is a group of formula or . Disclosed compounds have selective affinity to 5-HT6 and 5-HT2A receptors. Also described is a pharmaceutical composition containing said compounds and use of the said compounds in making a medicinal agent for treating diseased conditions of the central nervous system.

EFFECT: more effective treatment.

49 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

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